Nicotinic acid libraries

FIGURE 11.70 5-Substituted nicotinic acid and nicotinamide derivatives library. (From Fem ndez, J.-C. et al, Suzuki coupling reaction for the solid-phase preparation of 5-substitnted nicotinic acid derivatives. Tetrahedron Lett., 46, 581, 2005.)... 

Thus, from the Solanaceae, hyoscyamine, a tropane alkaloid, which we now know to be derived from ornithine and/or arginine (Arg, R, Scheme 12.7), and nicotine, derived from a combination of nicotinic acid (see Scheme 12.103, et seq.) and ornithine, serve as examples of alkaloids based on nonaromatic amino adds. In the benzylisoquinoline alkaloids, only morphine, arguably the first alkaloid isolated in purified form and known to be derived from tyrosine (Tyr, T), itself a prephenic acid derivative, is discussed. For the indole alkaloids, the single example of this rich family to be illustrated is vinblastine, a (relatively) recently isolated base of some medicinal value and which is shown to be composed of two different expressions of tryptophan (Trp, W) and mevalonate (Scheme 11.40). Finally, caffeine is chosen as the member of the purine alkaloids, a relatively small family of compounds but one of major commercial import and one whose biosynthesis is closely tied to the library of life. 

The subset screen of lactate bioisosteres and GPCR target class chemical libraries identified the singleton compound 8. The compound had a reproducible top effect of 70% and an EC50 of 1.6 pM. No activity against the nicotinic acid receptor (hu GPR109a) was detected (Scheme 21.5). 

A library of imidazo[l,2-a]pyridines was prepared by Shankaraiah and coworkers (Scheme 9.37)." Starting from 4-hydroxyphenylsulfide resin 311, 3 equiv of Boc-amino nicotinic acid 312 was added along with 3 equiv of EDC in DCM DMF(1 1), followed by... 

The physical properties of pyridine-containing acids make them particularly attractive starting points for combinatorial libraries for herbicide screens. Pyridines are relatively polar (log P = 0.60 for pyridine vs. 2.13 for benzene) (4) and the sinq>le unsubstituted acids are weakly acidic (nicotinic acid pKa 4.8). (5) Perhaps for these reasons, pyridine-containing acids have found considerable utility as herbicides. Representative examples of commercially successful, phloem mobile, pyridine acids (or dieir derivatives) include picloram, clopyralid, and triclopyr (synthetic auxins) imazethapyr and nicosulfuron (ALS inhibitors) clodinafop and haloxyfop (ACCase inhibitors). Each has a direct counterpart in the conesponding benzene series but, in these instances, the pyridine analog is invariably the superior herbicide. 

The final library consisted of 1320 nicotinic acids of general structure 2 derived from, in part, 36 amines as nucleophiles (2 of which failed), 24 boronic acids, and 5 stannanes. Each MiniKan contained 80 mg of resin, which, with a measured loading of 1.36 mmol/g, was capable of yielding 0.1088 mmol of disubstituted nicotinic acid product. The final product acids were cleaved from the resin with trifluoroacetic acid and isolated as discrete sanq>les. Each sanq>le was analyzed by LCMS and the expected molecular ion was found in >80% of the sanples (92% when failed iiq)uts were eliminated). In selected instances, H NMR analyses were also used to ascertain the success of individual reactions. Members of a 25-membered rehearsal library were hilly characterized the yield and purity of each member of this library are shown in Table 1. 

Table 1. Yield and Purity of a 25-Membered Rehearsal Library of 5,6-Disubstituted Nicotinic Acids...

In conclusion, a series of 10 combinatorial libraries consisting of 11,528 total conq)ounds were designed, prepared, and screened as potential herbicide leads. The libraries were chosen to deliver confounds with desirable physical properties, in diis case polar weak acids. The approach was illustrated with a series of 5,6-disubstituted nicotinic acids, prepared usii solid phase, combinatorial techniques. 

An even simpler protocol for performing nucleophilic substitutions (aminations) and Suzuki reactions in one pot was reported by the Organ group for the generation of a 42-member library of styrene-based nicotinic acetylcholine receptor (nAChR) antagonists (Scheme 6.21) [49]. After considerable experimentation, the authors found that simultaneous nucleophilic displacement and Suzuki coupling could be carried out very effectively by charging the microwave process vessel with the palladium catalyst (0.5 mol% palladium-on-charcoal), the boronic acid [R1B(OH)2], the... 

Two enz)mies of pyrrolidine alkaloid formation responsible for the conversion of putrescine to the N-methylpyrrolinium ion have been investigated in some detail. PMT, partially purified from cultures of Hyoscyamus niger and fully characterized from Datura stramonium, has been cloned by differential screening of complementary deoxyribonucleic acid (cDNA) libraries from high- and low-nicotine-yielding N. tabacum plants (Hibi et ah, 1994). The enzyme shows considerable sequence homology to spermidine synthase but is distinct from this enz)mie as it only shows PMT activity when expressed in Escherichia coli. MPO has been isolated in pure form from N. tabacum transformed root cultures (McLauchlan et ah, 1993). It is quite widely spread in... 

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